Opioids are a group of drugs that exhibit opium or morphine-like properties. They are employed primarily as moderate to strong analgesics, but have many other pharmacological effects as well, including drowsiness, respiratory depression, constipation, changes in mood, and mental clouding without a resulting loss of consciousness. Morphine and codeine are by far the most important naturally occurring opiate agonists. Substitution of the nitrogen atom of the morphinan ring of these compounds affects their pharmacologic properties. For example, morphinan derivatives having various nitrogen substituents exhibit partial agonist/antagonist activity or potent antagonist activity. Morphinan compounds comprising quaternary amines are also known. For example, N-oxides of certain morphinans have been variously reported to be less active than the corresponding tertiary amine.
Recent research has shown that morphinans comprising opiate receptor antagonists and; in particular, their respective quaternary amines are potent inhibitors of vascular endothelial growth factor (VEGF). VEGF inhibitors are important adjuncts in the treatment of various tumors and the treatment of macular degeneration. More recent work has suggested that VEGF inhibitory activity appears to be independent of the stereochemistry of the morphinan ring system. That is, (+)-morphinan quaternary compounds appear to inhibit VEGF as well as the pharmacologically active (−)-morphinan quaternary compounds. Thus, other (+)-morphinan derivatives such as (+)-morphinanium N-oxides may be useful as improved VEGF inhibitors because they do not interact with opiate receptors. There is a need, therefore, for processes for synthesizing (+)-morphinanium N-oxides.